Focus of Research for Clinicians

A systematic review of 166 clinical studies published between January 1966 and April 2010 examined the comparative effectiveness, benefits, and adverse effects of available monotherapy and two-drug combinations of medications for adults with type 2 diabetes. The review did not cover treatment of type 1 diabetes or gestational diabetes nor does it review evidence regarding the effectiveness of diet, exercise, and weight loss. The full report, listing all studies, is available at http://www.effectivehealthcare.ahrq.gov/diabetesmeds.cfm. This summary, based on the full report of research evidence, is provided to inform discussions with patients of options and to assist in decisionmaking along with consideration of a patient’s values and preferences. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background Information

The management of hyperglycemia is an important focus of treatment to achieve improved macrovascular and microvascular outcomes in patients with type 2 diabetes. Controlling blood-glucose levels often requires several strategies, including weight loss if needed, dietary control, increased physical activity, and antidiabetic medications.1

Treatment regimens include single drugs and combinations of drugs from different classes. Choosing among the available medications requires consideration of benefits, adverse effects, mechanism of action, and cost. In 2007, the Agency for Healthcare Research and Quality published its first systematic review on the comparative effectiveness of oral medications for type 2 diabetes. The 2011 update includes newer medications and two-drug combinations.

1 American Diabetes Association; European Association for the Study of Diabetes

Conclusion

Evidence on the comparative effectiveness of antidiabetic medications for long-term macrovascular and microvascular outcomes is limited. However, evidence is available on intermediate outcomes. Many antidiabetic medications given as monotherapy work equally well to lower blood glucose. Two-drug combinations decrease hemoglobin A1c (HbA1c) further. Most agents (except metformin [MET] and glucagon-like peptide-1 [GLP-1] receptor agonists) are associated with increases in weight. The risk of mild to moderate hypoglycemia varies—it is highest for second-generation sulfonylureas (SU) and is increased for some two-drug combinations over monotherapy. MET may cause gastrointestinal (GI) upset. A United States Food and Drug Administration (FDA) warning indicates that thiazolidinediones (TZD) are associated with increased risks for cardiac failure, cardiovascular events, hip and nonhip fractures, and other risks in some patients. Tables 1, 2, and 3 summarize evidence about benefits, adverse events, and long-term benefits.

MET/SU was associated with higher levels of hypoglycemia than were these combinations:

MET/TZD

MET/GLP-1 receptor agonist (liraglutide)

MET/basal insulin combinations were associated with lower rates of hypoglycemia than were
MET/premixed insulin combinations.

GI adverse events

MET/SU was associated with more GI adverse events than was SU/TZD.

Hip/nonhip fractures

Combination therapy with a TZD was associated with higher rates of bone fractures than was MET/SU.

FDA Alerts for TZDs

According to FDA boxed warnings, TZDs may cause or exacerbate CHF in some patients and are contraindicated in patients with serious or severe heart failure. In 2010, the FDA placed additional prescribing restrictions on rosiglitazone use for type 2 diabetes in response to data that suggested an elevated risk of cardiovascular events, including myocardial infarction and stroke. In 2011, the FDA released a Safety Announcement that the use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer (for more information visit www.fda.gov).

Gaps in Knowledge

Studies are needed to address the efficacy of treatments for hyperglycemia in patients with type 2 diabetes who have varying levels of underlying cardiovascular and renal disease, who come from different ethnic groups, or who have variant forms of type 2 diabetes.

Additional comparative studies are needed, including comparisons of newer medications, combinations with basal or premixed insulin and MET or other oral agents, and additional two-drug combinations.

Sufficient data on event rates are needed to analyze major clinically important outcomes, adverse events, and long-term complications of type 2 diabetes.

Clinical Outcomes Table 3: Long-Term Benefits

(Findings followed by evidence on specific comparisons.)

Studies examining long-term benefits were limited. Only low levels of evidence were available for long-term outcomes (except as noted below for Pio, which may provide benefit for renal function), making it difficult to draw conclusions.

Clinical Outcomes Long-Term Benefits: Monotherapy Versus Monotherapy

All-cause mortality

MET was associated with a lower risk of all-cause mortality when compared with SU.

There was insufficient evidence for all other comparisons, including:

DPP-4 inhibitor comparisons

RSG versus Pio combinations

Oral agent/insulin combinations

GLP-1 receptor agonist comparisons

All other combination therapy comparisons

Cardiovascular mortality

MET was associated with a slightly lower risk of cardiovascular mortality when compared with SU.

MET was associated with rates of cardiovascular mortality similar to those of TZDs.

Average Wholesale Prices for Diabetes Medicines

Drug Type

Generic

Brand

Dose

Price for 1-Month Supply: Generic

Price for 1-Month Supply: Brand

These prices are the Federal median price for generic medicines and the average wholesale price for brand name medicines rounded to the next $5. These prices come from Red Book: Pharmacy’s Fundamental Reference, 2011 Edition.

XR/XL = extended release

NA = not available as a generic

Biguanides

Metformin

Glucophage®

500 mg once a day

$25

$35

500 mg twice a day

$50

$70

500 mg three times a day

$75

$105

850 mg once a day

$40

$60

850 mg twice a day

$80

$115

850 mg three times a day

$120

$175

1,000 mg once a day

$45

$70

1,000 mg twice a day

$90

$140

Glucophage XR®

500 mg once a day

$25

$35

1,000 mg once a day

$50

$70

1,500 mg once a day

$75

$105

2,000 mg once a day

$100

$140

Second-Generation Sulfonylureas

Glimepiride

Amaryl®

1 mg once a day

$15

$20

2 mg once a day

$25

$35

4 mg once a day

$40

$60

8 mg once a day

$80

$120

Glipizide

Glucotrol®

5 mg once a day

$15

$25

10 mg once a day

$25

$40

10 mg twice a day

$50

$80

20 mg twice a day

$100

$160

Glucotrol XL®

5 mg once a day

$15

$25

20 mg once a day

$65

$90

Glyburide

Diabeta® Micronase®

2.5 mg twice a day

$40

$45

5 mg once a day

$30

$40

5 mg twice a day

$60

$80

Glynase PresTab®

1.5 mg once a day

$9

$30

3 mg once a day

$18

$45

6 mg twice a day

$72

$145

Meglitinides

Repaglinide

Prandin®

0.5 mg three times a day

NA

$255

1 mg three times a day

NA

$255

4 mg three times a day

NA

$505

Nateglinide

Starlix®

60 mg three times a day

NA

$195

120 mg three times a day

NA

$200

Thiazolidinediones

Pioglitazone

Actos®

15 mg once a day

NA

$180

30 mg once a day

NA

$275

45 mg once a day

NA

$300

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Sitagliptin

Januvia®

100 mg once a day

NA

$230

Saxagliptin

Onglyza®

2.5 mg–
5 mg once a day

NA

$220

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

Exenatide

Byetta®

Injection of 5 mcg twice a day

NA

$300

Injection of 10 mcg twice a day

NA

$330

Liraglutide

Victoza®

Injection of 0.6 mg once a day

NA

$160

Injection of 1.2 mg once a day

NA

$315

Injection of 1.8 mg once a day

NA

$470

What To Discuss With Your Patients

Establishing a goal for HbA1c and strategies to help accomplish that goal, including weight loss, exercise, and consistent use of medication.

Strategies to increase adherence, including creating a medication schedule, addressing the costs of medications, and reporting adverse effects in a timely manner.

The need for regular glucose testing and routine blood tests for HbA1c.

What side effects to expect from the chosen medicines, and when to contact you if side effects occur.

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Andrea Humphries, Ph.D., Thomas Workman, Ph.D., Ashok Balasubramanyam, M.D., and Michael Fordis, M.D.